Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy with incompletely understood pathogenesis and poor prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been demonstrated in several tumors and is partly associated with a more aggressive phenotype and a worse prognosis. In addition, targeting the EGFR tyrosine kinase represents a successful new therapeutic strategy, e.g. in non-small cell lung cancer. Therefore, we investigated the role of EGFR in ACC as a potential therapeutic target.
Methods: EGFR expression was analyzed by immunohistochemistry in 95 ACCs and 5 normal adrenals using paraffin sections and tissue arrays (scoring of expression: 03). Utilizing the clinical data from the German ACC registry, Kaplan Meier survival analyses were performed. In 30 patients the tumor DNA was sequenced for mutations of the hot spot exons 1921 of the EGFR gene. In addition, cells of the ACC cell line NCI-h295 were incubated with the EGFR antibody cetuximab (1100 μg/ml) and cell proliferation was measured by MTT tests.
Results: Immunohistochemistry revealed EGFR expression in 78% of ACCs. In 55/95 (58%) of the ACCs and 0/5 of the normal adrenals the expression level was judged as moderate-to-high (score 2 or 3). However, the expression level did not correlate with the clinical outcome in these patients. In addition, none of the sequenced tumor DNA samples showed a mutation in exon 1921. Cetuximab exhibited a dose dependent antiproliferative effect in NCI-H295 cells (cell viability: 1 μg/ml: 95±2%; 10 μg/ml 90±3%*; 100 μg/ml 85±4%* vs untreated control cells: 100±3%; *=P<0.01).
Conclusion: EGFR is overexpressed in the majority of ACC. Moreover, in vitro experiments demonstrated that inhibition of EGFR signalling lead to moderate growth inhibition in ACC cells. Therefore, in patients with ACC refractory to established cytotoxic therapies the experimental use of EGFR inhibitors (combined with cytotoxic therapy) seems to be justified.